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Identification of intrinsic growth modulators for intact CNS neurons after injury

ABSTRACT: Functional deficits persist after spinal cord injury (SCI) because axons in the adult mammalian central nervous system (CNS) fail to regenerate. However, modest levels of spontaneous functional recovery are typically observed after trauma, and are thought to be mediated by the plasticity of intact circuits. The mechanisms underlying intact circuit plasticity are not delineated. Here, we characterize the in vivo transcriptome of sprouting intact neurons from ngr1 null mice after partial SCI. We identify the lysophosphatidic acid signaling modulators Lppr1 and Lpar1 as intrinsic axon growth modulators for intact corticospinal motor neurons after adjacent injury. Furthermore, in vivo Lpar1 inhibition or Lppr1 overexpression enhances sprouting of intact corticospinal tract axons and yields greater functional recovery after unilateral brainstem lesion in wild type mice. Thus, the transcriptional profile of injury-induced sprouting of intact neurons reveals targets for therapeutic enhancement of axon growth initiation and new synapse formation.

ORGANISM(S): Mus musculus

PROVIDER: GSE94482 | GEO | 2017/03/13

SECONDARY ACCESSION(S): PRJNA369825

REPOSITORIES: GEO

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Project description:Primary afferent collateral sprouting (PACS) is a process whereby non-injured primary afferent neurons respond to some stimulus by extending new branches from existing axons. In the model used here (spared dermatome), the intact sensory neurons respond to the denervation of adjacent areas of skin by sprouting new axon branches into that adjacent denervated territory. Neurons of both the central and peripheral nervous systems undergo this process, which contributes to both adaptive and maladaptive plasticity. Investigations of gene expression changes associated with PACS can provide a better understanding of the molecular mechanisms controlling this process. Consequently, it can be used to develop treatment for spinal cord injury to promote functional recovery. In this study, we sought to identify gene expression changes in PACS using 20 Affymetrix Rat Genome 230 2.0 microarrays. The experiments were designed to discover global gene expression changes in non-injured DRG neurons undergoing PACS. T11 DRG neurons remained intact and undergo PACS after the cutaneous nerves of the adjacent segments (T9, T10, T12, and T13) were injured and regeneration of those injured nerves prevented by ligation. Thus, the T9, T10, T12, and T13 dermatomes were denervated, but the T11 dermatome remained intact. Axons of the T11dermatome (and thus housed in the T11 dorsal root ganglion (DRG)), extended new branches to innervate the T9, T10, T12, and T13 dermatomes. N.B.: This is NOT a spared root experiment. ALL spinal roots were non-injured. Peripheral nerves were used. A total of 20 Affymetrix Rat Genome 230 2.0 microarrays were analyzed: six naÃ¯ve controls, seven replicates at day 7 post-surgery (presumed to represent an â??initiation phaseâ??), and seven replicates at day 14 post-surgery (presumed to represent a â??maintenance phaseâ??). DRGs were NOT pooled onto microarrays. Each animal had its own microarray with T11 DRG sample which underwent 2-round amplification. After quality control analysis, one of the naÃ¯ve control microarrays was removed from further analysis.

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Identification of intrinsic growth modulators for intact CNS neurons after injury

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